1. Field of the Invention
The present invention relates to a medicine, a carrier for the medicine, and a method of treatment using the medicine, with or by which acoustic cavitation is caused by ultrasonic radiation and treatment or diagnosis is carried out by the action thereof.
2. Description of the Related Art
The treatment of malignant tumors by extracorporeal radiation of a focused ultrasound is less invasive and in principle superior with respect to physical strength declining and postoperative quality of life of patients as compared with surgical operation and the social value thereof is expected to be going up in the future. The treatment using a focused ultrasound includes two classes, namely thermal treatment which comprises raising the temperature of the affected part through absorption of the ultrasound by the relevant tissue, and chemical one utilizing the interaction between a chemical substance and the ultrasound. A method of treatment which belongs to the latter class and uses a substance capable of generating active oxygen species upon ultrasonic irradiation has been proposed by Umemura et al. (S. Umemura, et al.: Jpn J. Cancer Res., vol. 84, pp. 582–586 (1993)) and is called sonodynamic cancer treatment.
In sonodynamic cancer treatment acoustic cavitation is thought to play an important role in producing therapeutic effects. For this purpose, methods using physical means have so far exclusively been proposed for efficiently causing nucleation and collapse of acoustic cavitation. Thus, JP-A-H02-126848 (1990) describes a technology which comprises irradiating ultrasonic waves while changing the sound field at intervals of 1 to 100 msec. Taking notice of the fact that the ultrasonic irradiation time required for the nucleation of acoustic cavitation is 1 to 100 msec, this technology instructs that ultrasonic irradiation be made while changing the sound field from one to the other differing in wave front at such time intervals so that the acoustic cavitation nucleated by one sound field may be collapsed by the other sound field and this cycle may be repeated. By doing so, it becomes possible to improve the efficiency of acoustochemical effects by an order of magnitude as compared with the case where the sound field is not changed at the same ultrasonic power level. Further, in U.S. Pat. No. 5,523,058, there is described a technology according to which a wave form favorable to acoustic cavitation nucleation, which can generally be obtained in the presence of a reflector, can be obtained even when there is no reflector. According to this technology, a waveform favorable to acoustic cavitation nucleation is obtained by superposing one frequency component and the second harmonic component thereof on each other. Since when ultrasonic irradiation is applied to a patient, the reflector effect cannot always be expected, it is expected that this technology will contribute to the enhancement of effects and the improvement in safety in the ultrasonic irradiation treatment.
Further, in JP-B-H06-29196 (1994), there is described a method of chemically enhancing the antitumor effect of ultrasound which comprises using a substance capable of forming active oxygen species when exposed to the chemical action of ultrasound. The substances, for example porphyrin, used in this technology secondarily generate active oxygen species due to acoustic cavitation caused by ultrasonic waves. However, they cannot lower the cavitation threshold. On the contrary, WO 98/01131 describes a technique of lowering the cavitation threshold by means of an amphiphilic xanthene dye and causing acoustic cavitation by ultrasonic waves to thereby cause secondary generation of active oxygen species by the dye.
In the field of ultrasonic diagnosis, microbubble contrast agents comprising air or gas bubbles with low solubility as covered by a shell made of a protein, a surface active agent and/or the like are widely used. These contrast agents are effective in lowering the threshold of acoustic cavitation, as reported by A. A. Atchley in Ultrasonics, vol. 26, pp. 280–285 (1988). Using this property, E. C. Unger et al. proposed, in Am. J. Cardiol., vol. 81, p. 58, a thrombosis treatment agent comprising such a contrast agent and a thrombus-selective peptide bound to the surface of the contrast agent and intended to be used in combination with ultrasound. However, although such microbubbles themselves can facilitate the cavitation, they are not physiologically active in generating active oxygen species or the like upon ultrasonic irradiation. In their application in such thrombosis treatment agents as mentioned above, it is necessary to use them in combination with a thrombolytic agent. Furthermore, those bubbles which have a diameter of several micrometers and are effective as a contrast agent do not migrate from blood vessels to other organs, so that when the microbubble contrast agents known in the art are used as such, it is difficult to apply them to sites other than intravascular sites.
As mentioned above, some technologies have been proposed for efficiently producing biological actions of acoustic cavitation. By the way, a therapeutic agent to be used in sonodynamic treatment is required to have three functions, namely (1) the ability to accumulate to the tumor site, (2) the ability to lower the threshold of acoustic cavitation and (3) the ability to generate active oxygen species upon exposure to acoustic cavitation caused by ultrasonic waves. This requirement is partially satisfied by the method disclosed in WO 98/01131, namely the method comprising lowering the cavitation threshold by means of an amphiphilic xanthene dye and causing acoustic cavitation by ultrasonic waves to thereby cause secondary generation of active oxygen species by the dye. However, this method intends to make one substance perform the above three functions. Therefore, in particular in the function in secondarily generating active oxygen species in response to ultrasound-caused cavitation, the above dye is inferior to porphyrin dyes. This poses a problem.
On the other hand, stabilized bubbles produced by stabilizing air or gas bubbles with low solubility in water by means of a shell consisting of a protein or a surface active agent, when used as a contrast medium, show an effect of lowering the sound intensity for causing cavitation within blood vessels and therefore are expected to be applicable to intravascular treatment in combination with an appropriate drug. However, the drug so far combined with such stabilized gas is a thrombolytic agent or a DNA, and such drug does not particularly interact with cavitation but cavitation is only indirectly involved in the treatment, for example by promoting drug penetration into the affected part.